The primary objective of this proposal is to continue investigations of drug resistance in multiple myeloma. In addition to evaluating mechanisms of drug resistance, methods of preventing or circumventing resistance will be developed. In the past, this laboratory has shown that multiple drug resistance (MDR) develops in the majority of myeloma patients and that this resistance is due to the presence of P-glycoprotein (P-gly). This is an acquired resistance which is related to prior administration of vincristine and doxorubicin (Dox). We also extended our studies to malignant lymphomas and observed that P-gly was infrequently expressed among untreated lymphomas but was common in selected drug-refractory patients. Drug resistance due to enhanced drug efflux could be blocked by verapamil (V) and other chemosensitizing agents. Clinically, a subset of patients benefited from the addition of V to therapy; however, patients ultimately became resistant to the effects of V and their disease progressed. Still other patients had clinical drug resistance with no P-gly on their tumors, or, despite the presence of P-gly, did not respond to V. Possibilities which might explain the temporary response to V or no response at all include: (i) the chronic exposure of V with Dox selects for mechanisms of resistance that are unique and unaffected by V, (ii) mechanisms of MDR exist that are non-P-gly related and are not reversed by V or other chemosensitizers, (iii) the expression of P-gly is limited to well- differentiated plasma cells only, with the immature precursor cells being P-gly-negative. We will evaluate these possibilities by investigating the following specific aims: (1) evaluating mechanisms of Dox resistance in myeloma cells selected for resistance in the presence of V; (2) evaluating non-P-gly mechanisms of drug resistance that are not reversed by V of other known chemosensitizers; (3) determining if P-gly is related to B-cell differentiation in patients with multiple myeloma. New approaches to overcoming resistance that is unaffected by V will be analyzed. We have observed that V-selected cell lines are deficient in omicron6 methylguanine methyltransferase (MGMT). We will investigate genetic factors that control MGMT expression in the V-selected myeloma cell lines, and determine if the reduction in MGMT activity seen in these cell lines also occurs in patients who are treated with chronic V plus chemotherapy treatment. If MGMT activity decreases in patients then they may be more sensitive to nitrosoureas.